Infectious agents may contribute to the causation of up to 30% of cancers in humans, including viruses associated with liver, cervical, penile, and nasopharyngeal cancer, parasites with liver and bladder cancer, and the bacterium Helicobacter pylori with gastric cancer. The liver pathogen Helicobacter hepaticus was discovered five years ago in strain A/J mice being used in a bioassay in this Laboratory. Slowly progressing hepatitis in these mice culminates in a high incidence of benign and malignant liver tumors, providing an important animal model for study of mechanisms of infection-related cancer. We first tested the hypothesis that the tumors resulted from elaboration of genotoxicants, but obtained negative results from Ames' tests for mutagens and from analysis of ras and p53 genes for mutations. However, major genomic and biochemical changes were detected from an early stage of the infection, well before any overt pathology was noted. These have included production of superoxide in the cytoplasm of certain hepatocytes, increase in oxidatively-damaged DNA bases, complex changes in cytochromes P450 and glutathione S-transferases, and a major shift in the pattern of 32P-postlabeled DNA adducts. Based on these observations, we hypothesize that a tumor promotion-like phenomenon is involved in the causation of liver tumors by H. hepaticus. In support of this, we have found that natural infection with the bacterium resulted in a significant enhancement in both rate of appearance and rate of progression to malignancy of liver tumors initiated by neonatal administration of N-nitrosodimethylamine. Upregulation of cyclin D1 indicates dysregulation of cell cycle control. Further study of genomic and epigenetic changes is in progress, as well as development of an experimental infection model. Possible direct human relevance is being tested by attempts to infect patas monkeys, and by examination of human cases of unexplained hepatitis or liver cancer.